This application is rule 371 Application of PCT Application No. PCT/EP00/11995, filed Nov. 30, 2000, which claims priority to GB Application Serial No. 9928561.1, filed Dec. 2, 1999 and GB Application Serial No. 0003500.6, filed Feb. 15, 2000.
The present invention relates to certain novel compounds. In particular, the present invention relates to compounds that activate the alpha subtype of the human peroxisome proliferator activated receptor (xe2x80x9chPPAR alphaxe2x80x9d). The present invention also relates to methods for preparing the compounds and methods for prevention or treatment of PPAR alpha mediated diseases or conditions.
Several independent risk factors have been associated with cardiovascular disease. These include hypertension, increased fibrinogen levels, high levels of triglycerides, elevated LDL cholesterol, elevated total cholesterol, and low levels of HDL cholesterol. HMG CoA reductase inhibitors (xe2x80x9cstatinsxe2x80x9d) are useful for treating conditions characterized by high LDL-c levels. It has been shown that lowering LDL-c is not sufficient for reducing the risk of cardiovascular disease in some patients, particularly those with normal LDL-c levels. This population pool is identified by the independent risk factor of low HDL-c. The increased risk of cardiovascular disease associated with low HDL-c levels has not yet been successfully addressed by drug therapy (i.e., currently there are no drugs on the market that are useful for raising HDL-c  greater than 40%). (Bisgaier, C. L.; Pape, M. E. Curr. Pharm. Des. 1998, 4, 53-70).
Syndrome X (including metabolic syndrome) is loosely defined as a collection of abnormalities including hyperinsulinemia, obesity, elevated levels of trigycerdes, uric acid, fibrinogen, small dense LDL-c particles, and plasminogen activator inhibitor 1 (PAI-1), and decreased levels of HDL-c.
NIDDM is described as insulin resistance which in turn causes anomalous glucose output and a decrease in glucose uptake by skeletal muscle. These factors eventually lead to impaired glucose tolerance (IGT) and hyperinsulinemia.
Peroxisome Proliferator Activated Receptors (PPARs) are orphan receptors belonging to the steroid/retinoid receptor superfamily of ligand-activated transcription factors. See, for example, Willson, T. M. and Wahli, W., Curr. Opin. Chem. Biol., (1997), Vol. 1, pp 235-241.
Three mammalian Peroxisome Proliferator-Activated Receptors have been isolated and termed PPAR-alpha, PPAR-gamma, and PPAR-delta (also known as NUC1 or PPAR-beta). These PPARs regulate expression of target genes by binding to DNA sequence elements, termed PPAR response elements (PPRE). To date, PPRE""s have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism suggesting that PPARs play a pivotal role in the adipogenic signaling cascade and lipid homeostasis (H. Keller and W. Wahli, Trends Endoodn. Met 291-296, 4 (1993)).
Certain compounds that activate or otherwise interact with one or more of the PPARs have been implicated in the regulation of triglyceride and cholesterol levels in animal models. See, for example, U.S. Pat. No. 5,847,008 (Doebber et al.) and U.S. Pat. No. 5,859,051 (Adams et al.) and PCT publications WO 97/28149 (Leibowitz et al.) and WO99/04815 (Shimokawa et al.).
Fibrates are a class of drugs which may lower serum triglycerides 20-50%, lower LDL-c 10-15%, shift the LDL particle size from the more atherogenic small dense to normal dense LDL-c, and increase HDL-c 10-15%. Experimental evidence indicates that the effects of fibrates on serum lipids are mediated through activation of PPAR alpha. See, for example, B. Staels et al., Curr. Pharm. Des., 1-14, 3 (1), (1997). Activation of PPAR alpha results in transcription of enzymes that increase fatty acid catabolism and decrease de-novo fatty acid synthesis in the liver resulting in decreased triglyceride synthesis and VLDL-c production/secretion. In addition, PPAR alpha activation decreases production of apoC-III. Reduction in apoC-III, an inhibitor of LPL activity, increases clearance of VLDL-c. See, for example, J. Auwerx et al., Atherosclerosis, (Shannon, Irel), S29-S37, 124 (Suppl), (1996). PPAR alpha ligands may be useful for the treatment of dyslipidemia and cardiovascular disorders, see Fruchart, J. C., Duriez, P., and Staels, B., Curr. Opin. Lipidol. (1999), Vol 10, pp 245-257.
According to a first aspect of the invention there is provided a compound of formula (I) and pharmaceutically acceptable salts, solvates and hydrolysable esters thereof: 
wherein;
X1 represents O or S;
R1 and R2 independently represent H, halogen, xe2x80x94CH3 and xe2x80x94OCH3;
n represents 1 or 2;
X2 represents NH, NCH, or O;
One of Y and Z is N, and the other is O or S;
R3 represents phenyl or pyridyl (wherein the N is in position 2 or 3) and is optionally substituted by one or more halogen, NO2, NH2, CF3, OCF3, OC1-6 straight or branched alkyl, C1-6 straight or branched alkyl, alkenyl or alkynyl with the provision that when R3 is pyridyl, the N is unsubstituted;
R4 represents CF3 or CH3.
In another aspect, the present invention discloses a method for prevention or treatment of a human PPAR alpha (xe2x80x9chPPAR alphaxe2x80x9d) mediated disease or condition comprising administration of a therapeutically effective amount of a compound of this invention. hPPAR alpha mediated diseases or conditions include dyslipidemia including associated diabetic dyslipidemia and mixed dyslipidemia, syndrome X (as defined in this application this embraces metabolic syndrome), heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis, and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, and regulation of appetite and food intake in subjects suffering from disorders such as obesity, anorexia bulimia, and anorexia nervosa. Other diseases or conditions include inflammation. In particular, the compounds of this invention are useful in the treatment and prevention of cardiovascular diseases and conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia, and mixed dyslipidaemia.
In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, preferably in association with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention provides a compound of the invention for use in therapy, and in particular, in human medicine.
In another aspect, the present invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a hPPAR alpha mediated disease or condition.
In another aspect, the present invention provides a method of treatment of a patient suffering from a hPPAR alpha mediated disease or condition comprising the administration of a therapeutically effective amount of a compound of the invention.
As used herein, xe2x80x9ca compound of the inventionxe2x80x9d means a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or hydrolyzable ester thereof.
While hydrolyzable esters are included in the scope of this invention, the acids are preferred because the data suggests that while the esters are useful compounds, it may actually be the acids to which they hydrolyze that are the active compounds. Esters that hydrolyze readily can produce the carboxylic acid in the assay conditions or in vivo. Generally the carboxylic acid is active in both the binding and transient transfection assays, while the ester does not usually bind well but is active in the transient transfection assay presumably due to hydrolysis. Preferred hydrolysable esters are C1-6 alkyl esters wherein the alkyl group may be straight chain or branched chain. Methyl or ethyl esters are more preferred.
Preferably X1 represents O.
Preferably one of R1 and R2 represents H with R1 and R2 both representing H being more preferred.
Preferably n represents 1.
Preferably X2 represents NH.
Preferably Z represents N.
Preferably Y represents S.
Preferably R3 is phenyl, optionally substituted. Preferably R3 is mono or disubstituted. Preferably when R3 is pyridyl the N is in the 2 position. R3 preferably is monosubstituted in the para position and is more preferably phenyl. A preferred substituent is CF3.
Preferably R4 represents CH3.
While the preferred groups for each variable have generally been listed above separately for each variable, preferred compounds of this invention include those in which several or each variable in Formula (I) is selected from the preferred, more preferred, or most preferred groups for each variable. Therefore, this invention is intended to include all combinations of preferred, more preferred, and most preferred groups.
Preferably, the compounds of formula (I) are hPPAR alpha agonists. As used herein, by xe2x80x9cagonistxe2x80x9d, or xe2x80x9cactivating compoundxe2x80x9d, or xe2x80x9cactivatorxe2x80x9d, or the like, is meant those compounds which have a pKi of at least 6.0 to the relevant PPAR, for example hPPAR alpha, in the binding assay described below, and which achieve at least 50% activation of the relevant PPAR relative to the appropriate indicated positive control in the transfection assay described below at concentrations of 10xe2x88x925 M or less. More preferably, the compounds of this invention achieve 50% activation of human PPAR alpha in the transfection assay at concentrations of 10xe2x88x927 M or less.
Most preferably, the compounds of formula (I) are selective hPPAR alpha agonists. As used herein, a xe2x80x9cselective hPPAR alpha agonistxe2x80x9d is a hPPAR alpha agonist whose EC50 for PPAR alpha is at least 10 fold lower than its EC50 for PPAR gamma and PPAR delta. Such selective compounds may be referred to as xe2x80x9c10-fold selective.xe2x80x9d EC50 is defined in the transfection assay described below and is the concentration at which a compound achieves 50% of its maximum activity. Most preferred compounds are greater than 100-fold selective hPPAR alpha agonists.
Preferred compounds of the invention include:
2-methyl-2-[4-{[(4-methyl-2-[4-(fluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionic acid ethyl ester
N-methyl-2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionic acid ethyl ester
4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-carboxylic acid 4-(1-tertbutyloxycarbonyl-1-methylethoxy) benzyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-tertbutylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-isopropylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-nitrophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-aminophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-aminophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[3,4-dichlorophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[3-fluorotrifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-bromophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-ethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-phenylthiazol-5-ylcarbonyl)amino]-methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-fluorophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-chlorophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethoxyphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-methoxyphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-acetylenylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-trifluoromethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-trifuoromethyl-2-[4-tertbutylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-trifluoromethyl-2-[4-tertbutylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethylphenyl]-oxazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethyl-2-pyridyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[2-methoxy-4-{[(4-methyl-2-[4-trifluromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-trifluromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-trifluromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-isopropylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[2-methyl-4-{[(4-methyl-2-[4-isopropylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(5-methyl-2-[4-trifluoromethylphenyl]-thiazol-4-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(5-methyl-2-[4-trifluoromethylphenyl]-thiazol-4-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(5-methyl-2-[3-trifluoromethylphenyl]-thiazol-4-ylcarbonyl)amino]methyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(5-methyl-2-[3-trifluoromethylphenyl]-thiazol-4-ylcarbonyl)amino]methyl}phenoxy]propionic acid
More preferred compounds of the invention include:
2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionic acid ethyl ester
2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionic acid
N-methyl-2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]ethyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-tertbutylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-isopropylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-nitrophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[3,4-dichlorophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[3-fluorotrifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-bromophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-ethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-phenylthiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-fluorophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-chlorophenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-trifluoromethoxyphenyl]thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-methoxyphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-acetylenylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-trifluoromethyl-2-[4-trifluoromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethylphenyl]-oxazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[4-{[(4-methyl-2-[4-trifluromethyl-2-pyridyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
2-methyl-2-[2-methoxy-4-{[(4-methyl-2-[4-trifluromethylphenyl]-thiazol-5-ylcarbonyl)amino]methyl}phenoxy]propionic acid
A particularly preferred compound of the invention is 2-methyl-2-[4-{[(4-methyl-2-[trifluoromethylphenyl]thiazol-5-yl-carbonyl)amino]methyl}phenoxy]propionic acid.
The preferred compound listed above is a selective hPPAR alpha agonist.
It will also be appreciated by those skilled in the art that the compounds of the present invention may also be utilized in the form of a pharmaceutically acceptable salt or solvate thereof. The physiologically acceptable salts of the compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic, naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N,Nxe2x80x2-dibeenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine salts. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts and solvates.
The compounds of the invention and their pharmaceutically acceptable derivatives are conveniently administered in the form of pharmaceutical compositions. Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
While it is possible that compounds of the present invention may be therapeutically administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Accordingly, the present invention further provides for a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers therefore and, optionally, other therapeutic and/or prophylactic ingredients.
The formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds (xe2x80x9cactive ingredientxe2x80x9d) with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a other conventional excipients such as binding agents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (for example, potato starch or sodium starch glycollate) or wetting agents, such as sodium lauryl sulfate. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The tablets may be coated according to methods well-known in the art.
Alternatively, the compounds of the present invention may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, for example. Moreover, formulations containing these compounds may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents such as lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils) such as almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic add. Such preparations may also be formulated as suppositories, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacterostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freezeried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
The compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established diseases or symptoms. Moreover, it will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, preferably 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The formulations according to the invention may contain between 0.1-99% of the active ingredient, conveniently from 30-95% for tablets and capsules and 3-50% for liquid preparations.
The compound of formula (I) for use in the instant invention may be used in combination with other therapeutic agents for example, statins and/or other lipid lowering drugs for example MTP inhibitors and LDLR upregulators. The compounds of the invention may also be used in combination with antidiabetic agents, e.g. metformin, sulfonylureas and/or PPAR gamma agonists (for example thiazolidinediones such as e.g. Pioglitazone and Rosiglitazone). The compounds may also be used in combination with antihypertensive agents such as calcium channel antagonists and ACE inhibitors. The invention thus provides in a further aspect the use of a combination comprising a compound of formula (I) with a further therapeutic agent in the treatment of a hPPAR alpha mediated disease.
When the compounds of formula (I) are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation and may be formulated for administration. When formulated separately they may be provided in any convenient formulation, conveniently in such a manner as are known for such compounds in the art.
When a compound of formula (I) is used in combination with a second therapeutic agent active against the same hPPAR alpha mediated disease, the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
Compounds of this invention may be conveniently prepared by a general process wherein a moiety like (A) is coupled to an acid (B) using a peptide coupling reaction or by alkylation of (A) using a suitable non nucleophilic amine with an acid chloride (C). Preferably, R is 1-6 alkyl which can be hydrolyzed off to give an acid of Formula (I), or if readily hydrolyzable, the resulting ester can be administered. 
A preferred synthesis of (A) when X1 is O and X2 is NH (and R1 and R2 are H) is: 
Note that this synthesis is preferably carried out with the amine where the alcohol function is already alkylated with the acid side chain protected by R. For example, when n is 1, X1 is O, X2 is NH, Y is S, Z is N, R1 and R2 are H, and R3 is 4-F3C-phenyl: 
Some of the intermediates of type A are commercially available while others can be synthesized by techniques apparent to a person skilled in the art. The synthesis of intermediates of type B and C are illustrated below.
Compounds of the invention may be made by an alternative method in which compounds of formula (D) are reacted with ethyl 2-bromo-2 methyl propionate to produce the ethyl ester of the compound of formula (I) which may be hydrolysed to produce the free acid. 
Compounds of formula (D) may be prepared from the reaction between compounds of formula (B) and compounds of formula (E) with HOBT/EDC/NEt3 when X2 is NH or NCH3 or DIC/DMAP/NEt3 when X2 is O. 
The invention is further illustrated by the following examples which should not be construed as constituting a limitation thereto.

The procedure was as described in Stout, D. M. J. Med. Chem. 1983, 26(6), 808-13. To 4-methoxybenzyl amine (25 g, 0.18 mol; Aldrich) was added 46% HBr in H2O (106 ml, 0.9 mol; Aldrich). The reaction was refluxed overnight, then the reaction cooled to 0xc2x0 C. and neutralized to pH7 slowly with KOH(s). The reaction was allowed to stir for xcx9c30 min, then the solid filtered and dried. The solid was redissolved in hot MeOH, filtered and the solution cooled to afford 19 g (85%) intermediate 1. 1H NMR (DMSO-d6): xcex4 8.0 (bs, 1H), 7.2 (d, 2H), 6.75 (d, 2H), 3.85 (s, 2H), 3.50 (bs, 2H).

A solution of ethyl 2-chloroacetoacetate (35.3 g, 29.7 mL, 0.21 mol) and 4-(trifluoromethyl)thiobenzamide (44 g, 0.21 mol) in EtOH (300 mL) was refluxed overnight. After cooling to room temperature the solvent was removed in vacuo. The final product (intermediate 2) was recrystallized from a minimum of MeOH to afford 40 g (59%) of final product as a white solid. 1H NMR (CDCl3): xcex4 8.10 (d, 2H), 7.70 (d, 2H), 4.40 (q, 2H), 2.80 (s, 3H), 1.4 (t, 3H).

To intermediate 2 (1.84 g, 5.8 mmol) in THF was added 1 N LiOH (6 mL, 6 mmol) and the reaction stirred at rt. After xcx9c3 h, the reaction was neutralized with 1N HCl, extracted 3xc3x97100 mL EtOAc, dried over Na2SO4, filtered and the solvent removed under vacuum to afford 1.5 g (89%) intermediate 3 as a white solid. 1H NMR (DMSO-d6): xcex4 13.55 (bs, 1H), 8.25 (d, 2H), 7.95 (d, 2H), 2.75 (s, 3H).

To intermediate 3 (1 g, 7 mmol) in CH2Cl2/DMF (1:1) was added HOBT (565 mg, 4.2 mmol; Aldrich), EDC (800 mg, 4.2 mmol; Aldrich) and intermediate 1 (860 mg, 7 mmol). The reaction was stirred at rt for 18 h. The solvent was removed in vacuo, treated with H2O and extracted 3xc3x97100 mL CH2Cl2. The organic phases combined and washed with 1N HCl, dried over Na2SO4, filtered and evaporated to afford a mixture (N-substituted and N,O-substituted). The mixture was dissolved in MeOH and treated with 1N NaOH. The reaction was stirred 18 h at 50xc2x0 C. The solvent was removed in vacuo, and the residue was dissolved in CH2Cl2, washed with H2O, and dried over Na2SO4. The solvent was evaporated and the residue chromatographed (CH2Cl2/MeOH: 99/1) to afford 610 mg (47%) of intermediate 4 as a white solid. 1H NMR (DMSO-d6): xcex4 9.30 (s, 1H), 8.80 (t, 1H), 8.20 (d, 2H), 6.70 (d, 2H), 4.35 (d, 2H), 2.6 (s, 3H).
To a solution of P4S10 (0.2 mmol) in toluene (100 mL) was added NaHCO3 (2 mmol) and the mixture heated to reflux for ca. 30 min. The substituted benzamide (1 mmol) was added and the reaction stirred at 90xc2x0 C. for 1 h. The reaction was then evaporated to dryness, treated with brine (100 mL) and extracted with CH2Cl2 (2xc3x9750 mL). The organic phase dried, filtered, and evaporated to afford the final product.

The title compound was prepared as described in general procedure 1 to afford an orange solid (49%). 1H NMR (CDCl3): xcex4 7.7 (d, 2H), 7.4 (bs, 1H), 7.3 (d, 2H), 7.0 (bs, 1H), 1.2 (s, 9H).

The title compound was prepared as described in general procedure 1 to afford an orange solid (26%).
Mp: 150xc2x0 C.
To the substituted benzonitrile (1 mmol) in DMF (30 mL) is added dropwise DMF (21 mL) saturated with HCl(g) during 1 min. Thioacetamide (2 mmol) is then added and the reaction heated to 100xc2x0 C. for 1 h. HCl(g) is bubbled in for ca. 1 min and the stirring continued at 100xc2x0 C. for another 18 h. The reaction cooled to rt, treated with ice and extracted with Et2O (3xc3x97250 mL). The organic phase was washed with H2O (3xc3x97300 mL), dried over Na2SO4, filtered, and evaporated to dryness. The residue was washed with a mixture of isopropyl ether/pentane (1:3) to afford the final product.

The title compound was prepared as described in general procedure 2 to afford an orange solid (83%). 1H NMR (DMSO-d6): xcex4 10.1 (bs, 1H), 9.7 (bs, 1H), 8.1 (d, 2H), 7.9 (d, 2H).

The title compound was prepared as described in general procedure 2 to afford a yellow solid (45%).
MS m/z 207 (M+1).

The title compound was prepared as described in general procedure 2 to afford an orange solid (84%). 1H NMR (DMSO-d6): xcex4 10.5 (bs, 1H), 10.05 (bs, 1H), 8.1 (m, 3H).

To 4-bromobenzonitrile (1 mmol) was added the diethyldithiophosphate (1.2 equiv.). To the suspension was added H2O (ca. 100 mL) and the reaction heated to 80xc2x0 C. for ca. 2 h. The reaction cooled to rt and extracted with Et2O (3xc3x97100 mL). The organic phase was washed with sat. NaHCO3, dried over NaSO4 and evaporated to dryness leaving a yellow solid. The solid was rinsed with isopropyl ether and collected by filtration to afford the title compound as a yellow solid (55%).
MS m/z 214.

To the 4-ethylbenzamide (1 mmol) in toluene heated to reflux, was added Laweson""s reagent (1 equiv.). After the addidition was complete, the reaction was refluxed for 2 h. The reaction cooled to rt, treated with Et2O, washed with H2O and the organic phase dried over Na2SO4. The solution filtered, evaporated to dryness and the residue chromatographed with CH2Cl2/MeOH (98:2) to afford 3 g of the title compound as a yellow solid (55%). 1H NMR (DMSO-d6): xcex4 9.8 (bs, 1H), 9.4 (bs, 1H), 7.8 (d, 2H), 7.2 (d, 2H), 2.6 (q, 2H), 1.2 (t, 3H).
To a solution of the substituted thiobenzamide (1 mmol) in EtOH (100 mL) was added ethyl 2-chloroacetoacetate (1.1 mmol) and the mixture heated to reflux overnight. The reaction is cooled to room temperature and the solvent evaporated. The solid is crystallized from Et2O or hexane to afford the final product.

Intermediate 5 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (95%). 1H NMR (CDCl3): xcex4 8.0 (d, 2H), 7.55 (d, 2H), 4.45 (q, 2H), 3.85 (s, 3H), 2.5 (t, 3H), 1.45 (s, 9H).

Intermediate 6 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (97%). 1H NMR (CDCl3): xcex4 7.85 (d, 2H), 7.25 (d, 2H), 4.30 (q, 2H), 2.90 (st, 1H), 2.70 (s, 3H), 1.30 (t, 3H), 1.20 (d, 6H).

Intermediate 7 was reacted as described in general procedure 3 to afford the title compound as an yellow solid (74%). 1H NMR (CDCl3): xcex4 8.25 (d, 2H), 8.05 (d, 2H), 4.30 (q, 2H), 2.70 (s, 3H), 1.30 (t, 3H).

Intermediate 8 was reacted as described in general procedure 3 to afford the title compound as an pale yellow solid (77%). 1H NMR (CDCl3): xcex4 8.0 (d, 1H), 7.70 (dd, 1H), 7.40 (d, 1H), 4.30 (q, 2H), 2.70 (s, 3H), 1.3 (s, 3H).

Intermediate 9 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (40%). 1H NMR (DMSO-d6): xcex4 7.95 (m, 3H), 4.30 (q, 2H), 2.65 (s, 3H), 1.3 (s, 3H).

Intermediate 10 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (61%). 1H NMR (CDCl3): xcex4 7.70 (d, 2H), 7.55 (d, 2H), 4.25 (q, 2H), 2.70 (s, 3H), 1.30 (s, 3H).

Intermediate 11 was reacted as described in general procedure 3 to afford the title compound as a pale green solid (35%). 1H NMR (CDCl3): xcex4 7.70 (d, 2H), 7.15 (d, 2H), 4.15 (q, 2H), 2.50 (s, 3H), 2.50 (q, 2H), 1.15 (t, 3H), 1.05 (t, 3H).

The thiobenzamide (Aldrich) was reacted as described in general procedure 3 to afford the title compound as an off-white solid (28%). 1H NMR (CDCl3): xcex4 8.35 (d, 2H), 7.60 (m, 3H), 4.45 (q, 2H), 3.05 (s, 3H), 1.30 (t, 3H).

The 4-fluorothiobenzamide (Maybridge) was reacted as described in general procedure 3 to afford the title compound as an off-white solid (100%). 1H NMR (CDCl3): xcex4 7.75 (dd, 2H), 6.95 (t, 2H), 4.15 (q, 2H), 2.60 (s, 3H), 1.20 (t, 3H).

The 4-chlorothiobenzamide (Lancaster) was reacted as described in general procedure 3 to afford the title compound as an pale orange solid (54%). 1H NMR (CDCl3): xcex4 7.60 (d, 2H), 7.10 (d, 2H), 4.15 (q, 2H), 2.55 (s, 3H), 1.20 (t, 3H).

The 4-trifluoromethoxythiobenzamide (Interchim) was reacted as described in general procedure 3 to afford the title compound as an off-white solid (100%). 1H NMR (CDCl3): xcex4 7.90 (d, 2H), 7.15 (d, 2H), 4.25 (q, 2H), 2.65 (s, 3H), 1.30 (t, 3H).

The 4-methoxythiobenzamide (Lancaster) was reacted as described in general procedure 3 to afford the title compound as an off-white solid (52%). 1H NMR (DMSO-d6): xcex4 7.8 (d, 2H), 6.95 (d, 2H), 4.15 (q, 2H), 3.70 (s, 3H), 2.50 (s, 3H), 1.15 (t, 3H).
To a solution of the substituted thiazole ester (1 mmol) in EtOH (100 mL) was added (1.5 equiv.) NaOH (1N) and the mixture heated to 40xc2x0 C. overnight. The reaction is cooled to room temperature and the solution acidified with HCl (1N). The precipitate is collected washed with H2O and dried under vaccum to afford the final product.

Intermediate 12 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (64%). 1H NMR (CDCl3): xcex4 7.70 (d, 2H), 7.30 (d, 2H), 2.60 (t, 3H), 1.15 (s, 9H).

Intermediate 13 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (100%). 1H NMR (CDCl3): xcex4 7.75 (d, 2H), 7.15 (d, 2H), 2.85 (st, 1H), 2.65 (s, 3H), 1.15 (d, 6H).

Intermediate 14 was reacted as described in general procedure 4 to afford the title compound as a beige solid (99%). 1H NMR (DMSO-d6): xcex4 8.15 (d, 2H), 8.05 (d, 2H), 2.50 (s, 3H).

Intermediate 15 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (91%). 1H NMR (DMSO-d6): xcex4 8.35 (d, 1H), 8.05 (dd, 1H), 7.90 (d, 1H), 2.80 (s, 3H).

Intermediate 16 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (82%). 1H NMR (DMSO-d6): xcex4 8.05 (m, 3H), 2.75 (s, 3H).

Intermediate 17 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (87%). 1H NMR (DMSO-d6): xcex4 7.70 (d, 2H), 7.45 (d, 2H), 2.45 (s, 3H).

Intermediate 18 was reacted as described in general procedure 4 to afford the title compound as a pale green solid (79%). 1H NMR (DMSO-d6): xcex4 8.05 (d, 2H), 7.50 (d, 2H), 2.75 (q, 2H), 2.75 (s, 3H), 1.30 (t, 3H).

Intermediate 19 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (93%).
Mp 215xc2x0 C.

Intermediate 20 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (85%). 1H NMR (DMSO-d6): xcex4 8.0 (dd, 2H), 7.30 (t, 2H), 2.60 (s, 3H).

Intermediate 21 was reacted as described in general procedure 4 to afford the title compound as an pale orange solid (92%). 1H NMR (DMSO-d6): xcex4 7.95 (d, 2H), 7.55 (d, 2H), 2.60 (s, 3H).

Intermediate 22 was reacted as described in general procedure 4 to afford the title compound as an off-white solid (66%).
MS m/z 304 (M+1).

Intermediate 23 was reacted as described in general procedure 3 to afford the title compound as an off-white solid (98%). 1H NMR (DMSO-d6): xcex4 7.95 (d, 2H), 7.10 (d, 2H), 3.90 (s, 3H), 2.70 (s, 3H).

Intermediate 17 (1 mmol) was diluted in a mixture of MeCN/dioxane (100 mL) then Cul (0.05 equiv.) and 1,1,3,3-tertamethylguanidine (10 equiv.) was added and the reaction stirred 15 min under a N2 atmosphere. The reaction purged under vaccum and then trimethylsilylacetylene (1.1 equiv.) and Pd(PPh3)2Cl2 (0.1 equiv.) added and the reaction stirred at 80xc2x0 C. for 2 h. The solvent evaporated, the residue dissolved in CH2Cl2, washed with sat. NH4Cl, then NH4OH and finally brine. The organic layer dried over Na2SO4, filtered and evaporated. The crude product was chromatographed eluting with CH2Cl2 to afford the title compound as a beige solid (100%).
MS m/z 344 (M+1).

To intermediate 36 (1 mmol) in THF was added Bu4NF and the reaction stirred at rt for 2 h. The THF was evaporated, the residue dissolved in CH2Cl2, washed with sat. NH4Cl, then NH4OH and finally brine. The organic layer dried over Na2SO4, filtered and evaporated. The crude product was chromatographed eluting with CH2Cl2 to afford the title compound as white solid (44%).
MS m/z 272 (M+1).

Intermediate 37 was reacted as described in general procedure 4 to afford the title compound as a pale yellow solid (79%).
MS m/z 244 (M+1).

To the 4-trifluoromethylthiobenzamide (1 equiv., Lancaster) in DMF (150 mL) was added ethyl 2-chloro-4,4,4-trifluoroacetoacetate (1.5 equiv., Lancaster) and the reaction stirred at 100xc2x0 C. for 18 h. The reaction is cooled, concentrated and the residue chromatographed eluting with CH2Cl2. The yellow oil that is collected is titrated with hexane to afford the title compound as a white solid (13%).
MS m/z 369.

Intermediate 39 was reacted as described in general procedure 4 to afford the title compound as a white solid (94%). 1H NMR (DMSO-d6): xcex4 8.1 (d, 2H), 7.7 (d, 2H).

To intermediate 5 (1 equiv.) in EtOH (25 mL) was added ethyl 2-chloro-4,4,4-trifluoroacetoacetate (1 equiv., Lancaster) and the reaction stirred at reflux for 91 h. The reaction is cooled, concentrated, the residue dissolved in pentane and filtered. The solvent removed under vaccum to afford the title compound as a brown oil containing 2 compounds which was used without further purification

Intermediate 41 was reacted as described in general procedure 4 to afford the title compound as a mixture of 2 compounds. The mixture was chromatographed with cyclohexane/ethyl acetate (7/3) to recover the impurity then with CH2Cl2/MeOH (98/2) to recover the title compound as a white solid (9.7%).
MS m/z 329 (M+1).

To the 4-trifluoromethylthiobenzamide (1 equiv., Lancaster) in EtOH (100 mL) was added the ethyl 3-bromo-2-oxobutyrate (1.1 equiv.) and the reaction stirred at reflux for 18 h. The reaction cooled to rt, concentrated and the residue dissolved in CH2Cl2. The organic layer was washed with sat. NaHCO3 followed by H2O, dried over Na2HCO4, filtered and the solvent evaporated to dryness; The crude product was chromatographed eluting with CH2Cl2 to afford the title compound as a white solid (60%).

Intermediate 43 was reacted as described in general procedure 4 to afford the title compound as a white solid (74%).
MS m/z 287.

To the 3-trifluoromethylthiobenzamide (1 equiv., Lancaster) in EtOH (100 mL) was added the ethyl 3-bromo-2-oxobutyrate (1.1 equiv.) and the reaction stirred at reflux for 18 h. The reaction cooled to rt, concentrated and the residue dissolved in CH2Cl2. The organic layer was washed with sat. NaHCO3 followed by H2O, dried over Na2HCO4, filtered and the solvent evaporated to dryness; The crude product was chromatographed eluting with CH2Cl2 to afford the title compound as a yellow oil (81%).
MS m/z 315.

Intermediate 45 was reacted as described in general procedure 3 to afford the title compound as a white solid (92%).
MS m/z 288 (M+1).

Intermediate 5 (1 equiv.) in EtOH (100 mL) was added the ethyl 3-bromo-2-oxobutyrate (1.1 equiv.) and the reaction stirred at reflux for 18 h. The reaction cooled to rt, concentrated and the residue dissolved in CH2Cl2. The organic layer was washed with sat NaHCO3 followed by H2O, dried over Na2HCO4, filtered and the solvent evaporated to dryness; The crude product was chromatographed eluting with CH2Cl2 to afford the title compound as a pale yellow solid (56%).
Mp 108xc2x0 C.

Intermediate 47 was reacted as described in general procedure 4 to afford the title compound as a pale yellow solid (99%).
Mp 155xc2x0 C.

Intermediate 6 (1 equiv.) in EtOH (100 mL) was added the ethyl 3-bromo-2-oxobutyrate (1.1 equiv.) and the reaction stirred at reflux for 18 h. The reaction cooled to rt, concentrated and the residue dissolved in CH2Cl2. The organic layer was washed with sat. NaHCO3 followed by H2O, dried over Na2HCO4, filtered and the solvent evaporated to dryness; The crude product was chromatographed eluting with CH2Cl2 to afford the title compound as a yellow oil (48%).
MS m/z 289.

Intermediate 49 was reacted as described in general procedure 4 to afford the title compound as a white solid (73%).
MS m/z 262 (M+1).

To 4-(trifluoromethyl)benzamide (1 equiv.) in toluene (150 mL) was added droppwise the methyl 3-bromo-2-oxobutyrate (1 equiv.) and the reaction stirred at reflux for 20 h. The reaction was diluted with EtOAc (100 mL) and succesively washed with: NaOH (1N), HCl (1N) and water (3xc3x97100 mL), dried, filtered and evaporated to a syrup. The resulting mixture was purified by flash column chromatography [CH2Cl2 then CH2Cl2/MeOH (99.5:0.5)] to afford the title compound as a white solid (9%).
MS m/z 285.

Intermediate 51 was reacted as described in general procedure 4 to afford the title compound as a white solid (86%).
Mp 189.

(4-trifluoromethyl-2-pyridyl)thioamide (Lancaster) was reacted as described in general procedure 3 to afford the title compound as a white solid (48%).

Intermediate 53 was reacted as described in general procedure 4 to afford the title compound as a grey solid (84%). 1H NMR (DMSO-d6): xcex4 9.13 (d, 1H), 8.43 (dd, 1H), 8.35 (d, 1H), 2.75 (s, 3H).

To 4-hydroxy-3-methoxybenzylamine hydrochloride (1 equiv., Aldrich) in CH2Cl2 (300 mL) at 0xc2x0 C. was added Et3N (3 equiv.). Boc anhydride (0.95 equiv) in CH2Cl2 (50 mL) was added dropwise. The reaction was allowed to warm to rt and stirring continued for 18 h. The reaction was then poured into NaOH (1N) and the mixture extracted with NaOH (3xc3x9750 mL). The aqueous phases combined, acidified with HCl (1N) and extracted with CH2Cl2 (3xc3x97100 mL). The organic layers washed with H2O, dried over Na2SO4, filtered and the solvent removed under vaccum to afford the title compound as a clear oil (97%). 1H NMR (CDCl3): xcex4 6.75 (m, 3H), 5.55 (bs, 1H), 4.75 (bs, 1H), 4.15 (d, 2H), 3.80 (s, 3H), 1.40 (s, 9H).

To intermediate 56 (1 equiv.) in DMSO (100 mL) was added K2CO3 (3 equiv.) and ethyl 2-bromo-2-methylproprionate (1.3 equiv.). The reaction was stirred while heating at 100xc2x0 C. for 3 h. The reaction was poured onto ice and extracted with CH2Cl2 (3xc3x9750 mL). The combined organic layers were washed with NaOH (1N), then H2O and dried over Na2SO4. The solution filtered, evaporated to dryness and the crude product cristallized from hot hexane to afford the title compound as a brown solid (63%).
Mp 107-109xc2x0 C.

To intermediate 56 (1 equiv.) in CH2Cl2 (10 mL) at rt was added droppwise CF3COOH (7 equiv.) and the reaction stirred at rt for 18 h. The reaction was evaporated to dryness, treated with a sat. K2CO3 solution and extracted with CH2Cl2 (3xc3x97150 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as an oil (100%).
MS m/z 267.

To 4-methoxy-3-methylbenzalehyde (1 equiv., Acros) in EtOH (150 mL) at rt was added H2NOH,HCl (1.6 equiv.), (3 equiv.) NaOAc in 150 mL H2O and the reaction stirred for 2 h. The EtOH was evaporated, and the residue extracted with CH2Cl2 (3xc3x9750 mL). The combined organic layers were washed with H2O, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a white solid (93%).
Mp 71-73xc2x0 C.

To intermediate 58 (1 equiv.) in MeOH (200 mL) at rt was added [MeCO2]NH4 (6 equiv.), Pd/C (0.01 equiv.) and molecular sieves. The reaction was then heated to reflux for 18 h. The reaction was filtered through celite, evaporated to dryness and treated with HCl (1N). The aqueous layer was washed with CH2Cl2, filtered, basified to pH greater than 14 and extracted with CH2Cl2 (3xc3x9750 mL). The combined organic layers were washed with H2O, dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as an oil (46%).
MS m/z 151.

Intermediate 59 (1 equiv.) in excess 40% HBr/H2O (Aldrich) was refluxed for 18 h. The reaction was then evaporated to dryness to afford the title compound hydrobromide salt as a grey solid (97%).
Mp 235-237xc2x0 C.

To Intermediate 60 (1 equiv.) in CH2Cl2 (300 mL) at 0xc2x0 C. was added Et3N (3 equiv.). Boc anhydride (0.95 equiv.) in CH2Cl2 (50 mL) was added dropwise. The reaction was allowed to warm to rt and stirring continued for 18 h. HCl (1N) was added and the reaction extracted with CH2Cl2 (3xc3x97100 mL). The organic layers washed with H2O, dried over Na2SO4, filtered and the solvent removed under vaccum to afford the title compound as a white solid (96%).
Mp 105-107xc2x0 C.

To intermediate 61 (1 equiv.) in DMF (150 mL) was added K2CO3 (3 equiv.) and the reaction heated to 70xc2x0 C. Ethyl 2-bromo-2-methylproprionate (1.3 equiv.) was added droppwise and the reaction was stirred for 72 h at 70xc2x0 C. The reaction was poured onto ice and extracted with CH2Cl2 (3xc3x97150 mL). The combined organic layers were washed with NaOH (0.5N), then H2O and dried over Na2SO4. The solution filtered, evaporated to dryness to afford the title compound as an oil (69%). 1H NMR (CDCl3): xcex4 7.05 (d, 1H), 6.90 (dd, 1H), 6.60 (d, 1H), 4.80 (bs, 1H), 4.25 (q, 2H), 4.20 (d, 2H), 2.20 (s, 3H), 1.60 (s, 6H), 1.45 (s, 9H), 1.25 (t, 3H).

To intermediate 62 (1 equiv.) in CH2Cl2 (10 mL) at rt was added dropwise CF3COOH (7 equiv.) and the reaction stirred at rt for 18 h. The reaction was evaporated to dryness, treated with a sat. K2CO3 solution and extracted with CH2Cl2 (3xc3x97150 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as an oil (82%). 1H NMR (CDCl3): xcex4 7.00 (d, 1H), 6.90 (dd, 1H), 6.55 (d, 1H), 4.20 (q, 2H), 3.70 (s, 2H), 2.15 (s, 3H), 1.85 (bs, 2H), 1.50 (s, 6H), 1.20 (t, 3H).

To 4-hydroxybenzaldehyde (1 equiv.) in DMF (150 mL) was added NaH (1.5 equiv.) and the reaction stirred at 80xc2x0 C. for 30 min. Ethyl 2-bromo-2-methylproprionate (1.2 equiv.) was added dropwise and the reaction was stirred for 24 h at 80xc2x0 C. The reaction was evaporated to dryness, the residue treated with NaOH and extracted with CH2Cl2 (5xc3x97100 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent evaporated to to afford crude intermediate 64. After chromatography eluting with CH2Cl2/MeOH (98:2) the title compound was obtained as an oil (20%). 1H NMR (CDCl3): xcex4 9.80 (s, 1H), 7.75 (d, 2H), 6.80 (d, 2H), 1.55 (s, 6H), 1.3 (s, 9H).

To intermediate 64 (1 equiv.) in MeOH (50 mL) at rt was added NaBH4 (1 equiv.) and the reaction stirred at rt while it was followed by tic [CH2Cl2/MeOH (98:2); Rf=0.45]. When all the starting material had disappeared, the solvent was evaporated to dryness, the residue treated with H2O and extracted with CH2Cl2 (3xc3x9750 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness to afford the title compound as a semi-solid (100%). 1H NMR (CDCl3): xcex4 7.20 (d, 2H), 6.80 (d, 2H), 4.55 (s, 2H), 1.50 (s, 6H), 1.35 (s, 9H).

To the 4-hydroxyphenethyl amine (1 equiv.) in DMF (75 mL) at rt was added HOBT (1.1 equiv.), EDC (1.1 equiv.) and Et3N (1.5 equiv.). To the mixture was added dropwise intermediate 3 in DMF and the reaction was stirred at rt for 18 h. The reaction was evaporated to dryness, treated with a HCl (1N) and extracted with EtOAc (3xc3x97150 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to dryness. The crude intermediate 66 was chromatogaphed eluting with CH2Cl2/MeOH (9:1) to afford the title compound as a white solid (64%). 1H NMR (CDCl3): xcex4 9.2 (s, 1H), 8.40 (t, 3H), 8.10 (d, 2H), 7.85 (d, 2H), 7.05 (d, 2H), 6.70 (d, 2H), 3.40 (m, 2H), 2.70 (m, 2H), 2.60 (s, 3H).